AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease

Int J Mol Sci. 2022 Jan 4;23(1):528. doi: 10.3390/ijms23010528.


AGC1/Aralar/Slc25a12 is the mitochondrial carrier of aspartate-glutamate, the regulatory component of the NADH malate-aspartate shuttle (MAS) that transfers cytosolic redox power to neuronal mitochondria. The deficiency in AGC1/Aralar leads to the human rare disease named "early infantile epileptic encephalopathy 39" (EIEE 39, OMIM # 612949) characterized by epilepsy, hypotonia, arrested psychomotor neurodevelopment, hypo myelination and a drastic drop in brain aspartate (Asp) and N-acetylaspartate (NAA). Current evidence suggest that neurons are the main brain cell type expressing Aralar. However, paradoxically, glial functions such as myelin and Glutamine (Gln) synthesis are markedly impaired in AGC1 deficiency. Herein, we discuss the role of the AGC1/Aralar-MAS pathway in neuronal functions such as Asp and NAA synthesis, lactate use, respiration on glucose, glutamate (Glu) oxidation and other neurometabolic aspects. The possible mechanism triggering the pathophysiological findings in AGC1 deficiency, such as epilepsy and postnatal hypomyelination observed in humans and mice, are also included. Many of these mechanisms arise from findings in the aralar-KO mice model that extensively recapitulate the human disease including the astroglial failure to synthesize Gln and the dopamine (DA) mishandling in the nigrostriatal system. Epilepsy and DA mishandling are a direct consequence of the metabolic defect in neurons due to AGC1/Aralar deficiency. However, the deficits in myelin and Gln synthesis may be a consequence of neuronal affectation or a direct effect of AGC1/Aralar deficiency in glial cells. Further research is needed to clarify this question and delineate the transcellular metabolic fluxes that control brain functions. Finally, we discuss therapeutic approaches successfully used in AGC1-deficient patients and mice.

Keywords: AGC1/Aralar deficiency; malate-aspartate shuttle; mitochondrial aspartate-glutamate carrier; mitochondrial disorders; mitochondrial function.

Publication types

  • Review

MeSH terms

  • Aggrecans / deficiency
  • Aggrecans / genetics*
  • Aggrecans / metabolism
  • Amino Acid Transport Systems, Acidic / deficiency*
  • Amino Acid Transport Systems, Acidic / metabolism
  • Animals
  • Antiporters / deficiency*
  • Antiporters / metabolism
  • Biomarkers
  • Brain / metabolism
  • Combined Modality Therapy
  • Disease Management
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Energy Metabolism
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Glutamic Acid / metabolism
  • Hereditary Central Nervous System Demyelinating Diseases / diagnosis
  • Hereditary Central Nervous System Demyelinating Diseases / etiology*
  • Hereditary Central Nervous System Demyelinating Diseases / metabolism*
  • Hereditary Central Nervous System Demyelinating Diseases / therapy
  • Humans
  • Malates / metabolism
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Diseases / diagnosis
  • Mitochondrial Diseases / etiology*
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Diseases / therapy
  • Myelin Sheath / metabolism
  • Oxidation-Reduction
  • Phenotype
  • Psychomotor Disorders / diagnosis
  • Psychomotor Disorders / etiology*
  • Psychomotor Disorders / metabolism*
  • Psychomotor Disorders / therapy


  • ACAN protein, human
  • Aggrecans
  • Amino Acid Transport Systems, Acidic
  • Antiporters
  • Biomarkers
  • Malates
  • Glutamic Acid
  • malic acid

Supplementary concepts

  • Hypomyelination, Global Cerebral